tbuckley/cabot-search huggingface dataset:
NIMG-64. INTRAOPERATIVE LANGUAGE MAPPING USING GAMMA-BAND MODULATIONS OF ELECTROCORTICOGRAM (ECOG) INDUCED BY WORD/SOUND CATEGORIZATION TASK: VALIDATION WITH REPRODUCIBLE SPEECH ARRESTS DURING LINGUISTIC TASKS
Authors: Israt Tasnim, Nuri Ince, Sujit Prabhu, Kyle Noll, Chandra Swamy, Katherine Connelly, Priscella Asman, Tummala Sudhakar, Sarah Prinsloo, Chibawanye Ene, Roxana Grasu, Ho-Ling Liu, Matthew Muir, Shreyas Bhavsar, Vinodh Kumar
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE Determination of the correlation between gamma-band modulations of electrocorticogram (ECoG) induced by linguistic tasks and reproducible speech arrests caused by bipolar direct cortical stimulations (DCS). METHODS 3 subjects (age 39, 56, 64 years) with left temporal lobe glioma underwent surgery involving awake craniotomy. A 4x8 ECoG electrode grid (2.3mm contact exposure, 1cm contact spacing) was placed above the respective tumor area. A MATLAB-Simulink based real-time software system running on a portable laptop computer was used to map gamma-band modulations as a 2D heat map while the subjects engaged in different linguistic tasks: word/sound categorization by pressing a button, object naming, action naming, written descriptive naming, and auditory descriptive naming. Auditory stimulus was applied during word/sound categorization task (duration 300 – 500ms), auditory descriptive naming ( &amp;gt; 1s); other tasks involved visual stimulus only. The subjects repeated the four naming tasks while bipolar DCS (2/4/6 mA, 60Hz, 2s) was applied at different electrode pairs. RESULTS The electrodes having stronger gamma-band modulations were distinct for different tasks. Reproducible speech arrests occurred during object, action, auditory naming tasks while stimulating specific electrode pairs, even though not all these electrodes had strong activations during these tasks. Across all subjects these electrodes had strong activations consistently during word/sound categorization tasks, starting as early as 250ms and lasting even after the auditory stimuli were terminated (~ 650ms). The longer activations can be associated with word recognition process. The subjects self-reported about having difficulty in comprehension rather than speech production during speech arrests. 3D brain rendering using MRI images showed that the speech arrest electrodes were identically located on the superior temporal gyrus, inferior to central sulcus for all 3 subjects. CONCLUSION Intraoperative language mapping guided by gamma-band ECoG modulations induced by word/sound categorization tasks can be utilized to localize eloquent cortex associated with auditory processing.
CTNI-46. PIVOTAL STUDY TO EVALUATE SAFETY AND EFFICACY OF EXABLATE MODEL 4000 USING MICROBUBBLE RESONATORS TO TEMPORARILY MEDIATE BLOOD-BRAIN BARRIER DISRUPTION FOR LIQUID BIOPSY IN GLIOBLASTOMA (LIBERATE)
Authors: Manmeet Ahluwalia, John de Groot, John Lee, Alon Mogilner, Theodore H Schwartz, Terry Burns, Bhavya Shah, Michael McDermott, Chetan Bettegowda, Atulya Khosla, Arjun Sahgal, Mark Mishra, Achal S Achrol, Nir Lipsman, Graeme Woodworth
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Glioblastoma (GBM) has dismal outcome of 14-16 months. One of the challenges of drug development in GBM is lack of requisite circulating-free (cfDNA) in blood samples to develop biomarker driven targeted therapy trials. The Exablate focused ultrasound with circulating microbubble resonators uses the concept of real-time imaging to treat small target spots focusing energy in a non-invasive manner, thereby disrupting the Blood-Brain Barrier (BBBD) with potential to increase cfDNA in blood. METHODS LIBERATE is a prospective, multi-center, self-controlled pivotal ongoing clinical trial in subjects with suspected GBM evaluating the safety and effectiveness of Exablate Model 4000 to disrupt BBB to achieve a greater proportion of cfDNA in samples taken post-BBB disruption as compared to the sample taken before BBBD. Fifty eligible subjects with suspected GBM who are scheduled to undergo brain tumor resection or biopsy at 10 centers in the U.S. will participate in this study. The primary endpoint is defined for each subject as ratio between his/her cfDNA amount found in the blood sample 1-hour post-BBBD procedure compared to the cfDNA amount found in the blood sample collected pre-BBBD procedure. This study proposes to demonstrate that on average there is at least 2-fold increase in cfDNA (measured by central laboratory) at 1 hour post BBBD. Confirmatory secondary analysis will evaluate correlation between patterns obtained in panel of biomarkers evaluated in the resected tumor tissue and/or biopsy sample and blood sample collected 1-hour post-BBBD. Exploratory endpoints will include: (1) sensitivity of detection of known somatic mutations in the circulating blood samples (circulating tumor DNA) before and after BBBD, (2) time of greatest yield of cfDNA in the samples collected post BBBD blood samples (at 30 min, 1-hour, 2-hour and 3-hour) to determine time of greatest yield, (3) correlation of biomarkers between the imaging and the post-BBBD biomarker samples. (NCT05383872)
QLTI-02. AUTOMATED INTRAOPERATIVE RESECTION TECHNOLOGY GENERATES INCREASED TISSUE YIELD AND IMPROVED BIOLOGICAL PRESERVATION OF BRAIN TUMOR SPECIMENS FOR NEURO-ONCOLOGY RESEARCH
Authors: Arabinda Das, Arunprasad Gunasekaran, Heather R Stephens, Penny Sekerak, Joseph Mark, Daniel G McDonald, Milad Yazdani, Connor Stephenson, Cynthia A Welsh, Libby Kosnik Infinger, William A Vandergrift, Shikhar Mehrotra, Abhay K Varma, Pierre Giglio, Sunil J Patel, Bruce M Frankel, Alicia Zukas, David Cachia, Scott M Lindhorst
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GB) is an aggressive tumor showing extensive intertumoral and intratumoral heterogeneity. While preserving as much surrounding normal brain tissue as possible, neurosurgeons must aim to harvest maximal tumor tissue from a variety of tumor locations in an effort to capture heterogenic samples in high volume for molecular and pathologic diagnosis and translational research. A key challenge is the ability to consistently procure high-quality biologically active specimens. In this investigation, we implemented an automated intraoperative system to eliminate inconsistencies in the methodology of tissue collection, handling, and biological preservation immediately in the OR suite to establish a repeatable, standardized practice for obtaining high-quality tissue samples without the need for additional staff. Through this process, we were able to characterize matched specimens from GB patients or GB tumors from corresponding GB-allograft mice and compare the quality of traditional handling and collection processes of intraoperative tissue used in most neurosurgical operating rooms versus an automated resection, collection, and biological preservation system (APS) that captures, preserves, and biologically maintains tissue in a prescribed and controlled microenvironment. Matched specimens/or tissues were then processed in parallel at various time points and temperatures, evaluating viability, RNA and protein concentrations, and isolation of GB cell lines. We found that APS-derived GB slices stored in an APS modified medium remained viable and maintained high-quality RNA and protein concentration for up to 24 hours. Our results showed that primary GB cell cultures derived in this manner had improved growth over the widely used collection and preservation methods. Currently, we are continuing the investigation of collected samples in brain tumor animal models to further understand potential differences within the tumor region harvested and the cellular changes that occur over time. Our hope is this research will lead to new discoveries in the diagnosis and treatment of brain tumors.
BIOM-25. DETERMINATION OF LEVELS OF SMALL MOLECULAR WEIGHT THIOLS AND DISULFIDES IN MOUSE AND HUMAN NORMAL BRAIN AND GLIOBLASTOMA TISSUE
Authors: Kamal Shaik, Tigran Margaryan, Nader Sanai, Artak Tovmasyan
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Small molecular weight (SMW) thiols play an essential role in many biochemical processes, particularly in maintaining redox homeostasis. Herein, we report on the development and qualification of a sensitive and rapid LC-MS/MS method for the determination of oxidative stress biomarkers glutathione (GSH), cysteine (Cys), glutathione disulfide (GSSG), cystine (CySS), as well as the interrelated precursors and products methionine (Met), homocysteine (Hcy), cystathionine (Cysth), gamma glutamyl-cysteine (Glu-Cys), and cysteinylglycine (Cys-Gly) in both mouse and human normal brain and glioblastoma tissue. METHODS Mouse and human tissue samples were homogenized with N-ethylmaleimide solution to prevent thiol oxidation. Analytes were then extracted from homogenate samples by protein precipitation with 2% formic acid in acetonitrile. Separate calibration curves were prepared for thiols and disulfides in analytical solutions using stable isotope-labeled internal standards (IS). Three levels of quality control samples were prepared in mouse and human brain homogenates. The detection was performed on Sciex QTRAP 6500+ mass spectrometer in positive electrospray ionization mode. RESULTS The concentration ranges of 0.04-40 µmol/L for Glu-Cys/Hcy, 4-400 µmol/L for Met/GSH/Cys/Cys-Gly and 0.05-20 µmol/L for GSSG/CySS/Cysth were established using a linear regression model. A gradient elution was applied on Intrada Amino Acid column to achieve the optimal chromatographic separation with a 5 minute total run time. At least three precision and accuracy runs were conducted on different days. The stability of analytes in biological matrix and in analytical solutions has been tested at room temperature, 4 °C, and -80 °C for appropriate sample preparation, analysis, and storage. CONCLUSIONS A bioanalytical method to quantify a panel of SMW thiols and disulfides has been successfully developed, qualified, and utilized to assess the levels of these biomolecules in mouse normal brain and glioblastoma tissue as well as in glioblastoma tissue of patients enrolled in the sonodynamic therapy clinical trial (NCT04559685).
EXTH-17. COMBINATION OF HDAC INHIBITOR AND PI3K/MTOR INHIBITOR SYNERGISTICALLY INDUCES APOPTOSIS IN DIPG
Authors: Katie Barnett, HyukJean Kwon, Eric Raabe, Charles Eberhart
Journal: Neuro-Oncology (2022)

Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a pediatric brain tumor characterized by epigenetic dysregulation with median survival of 9-11 months. Currently, radiation is the only therapy option, and therefore calls for a new, effective treatment method. RG2833 is a brain penetrant, selective HDAC 1/3 inhibitor. Western blot confirmed that RG2833 treatment alone downregulates the NFkB pathway in multiple DIPG cell lines. We showed that RG2833 treatment decreases expression of NFkB regulated anti-apoptotic genes XIAP, BCL-2, and BCL-XL in vitro. In vivo results in DIPG flank tumors confirmed that BCL-2 and BCL-XL expression are decreased with RG2833 treatment. We have also confirmed through Western blot that RG2833 treatment induces p16, p21, and p27 expression, which negatively regulate cell cycle progression, in multiple DIPG cell lines. RNAseq data showed that PI3K/mTOR pathway is upregulated in DIPG after RG2833 treatment. Paxalisib is a brain penetrant PI3K/mTOR inhibitor currently in clinical trials for DIPG. We hypothesized that RG2833 and paxalisib combination treatment would yield synergistic effects. RG2833 synergizes with paxalisib to suppress growth as measured by CellTiterBlue. ZIP synergy scores calculated by SynergyFinder were 10.5 for SUDIPG06 and 9.2 for HSJD007. Western blot demonstrated that combination treatment induced c-PARP and FOXO1 in the SUDIPG06 cell line, and decreased p-RB expression in HSJD007 cell line. Induction of c-PARP indicates increased apoptosis, and decreased p-RB expression indicates decreased cell proliferation. In vivo experiments evaluating the efficacy of combination treatment are in progress. Our data suggest the combination of RG2833 and paxalisib may be a promising treatment option for DIPG.
INNV-29. MULTISPECTRAL ANALYSIS FOR INTRA-OPERATIVE CHARACTERIZATION OF BRAIN TUMOURS, MARGINS OF RESECTION, AND ELOQUENT AREAS ACTIVATION – PRELIMINARY RESULTS
Authors: Giulio Anichini, Hu Zepeng, Maria Leiloglu, Iani Gayo, Neekhil Patel, Nelofer Syed, Dipankar Nandi, Kevin O’Neill, Dan Elson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND The identification of intrinsic brain tumours’ boundaries and their anatomical relationship with eloquent connectomes is one of the main challenges in neurosurgery. Several new intra-operative spectroscopic technologies have been recently investigated for this purpose. Multispectral imaging (MSI) analysis is based on analysis of reflected light, divided in specific wavelengths ranges across the electromagnetic spectrum. By doing so, it can identify wavelengths invisible to the naked eye, and make them visible by applying specific filters. METHODS We have used MSI to acquire intraoperative images during brain tumours surgeries. The MSI camera has been adapted to be connected to the intra-operative microscope and acquire a stack of images of different spectra to be analysed on a separate time. The focus of the images acquisition includes tumour structure, its margins, and eloquent connectomes during awake surgery or neurostimulation to analyse the possibility of different perfusion signal during activation. Image segmentation using K-mean clustering has been used to detect structural information and identify tumour’s area and tumour’s margins, while oxygen maps have been created using linear least squares regression to detect areas of metabolic activity. RESULTS Twenty-three patients have been enrolled in the current study at the time of this submission. We have analysed the intra-operative acquisition using intra-operative microscope picture, pre- and post-operative MRI scan, and neurophysiological findings as ground truth. Our preliminary results show that MSI is a potential additional technology to visually show tumour core, margins, and different degree of perfusions on the tissues analysed during tumour surgery. Although on a very limited subgroup of patients, MSI seems to be reliable in identify eloquent areas activation during awake surgery. These results are promising and warrant more data acquisition to be confirmed.
NCMP-14. NEUROTOXICITY AFTER A SINGLE CYCLE OF INTRAVENOUS CYTARABINE
Authors: John Herbst, Christian Grommes, Lauren Schaff
Journal: Neuro-Oncology (2022)

Abstract Cytarabine neurotoxicity is well-documented, typically occurring after intrathecal treatment or a cumulative systemic dose of 36 g/m2. Encephalopathy, myelopathy, and acute cerebellar syndrome have all been described, with risk factors including advanced age and renal dysfunction. Here, we report a case of acute cerebellar syndrome after a single cycle of intravenous cytarabine 3 g/m2. This 65 year old man with history of chronic kidney disease (baseline creatinine 2.0 mg/dL) and primary central nervous system lymphoma had unconfirmed complete response after induction therapy with rituximab, methotrexate, and vincristine. Methotrexate was dosed between 1 -2 g/m2 due to renal dysfunction and delayed clearance. Given patient’s performance status and comorbidities, high-dose cytarabine consolidation was chosen. He received 3 g/m2 intravenously on days 1 and 2 of a 28-day cycle. On day 5, he developed acute truncal ataxia and was no longer able to sit or stand unsupported. He then presented to the emergency department on day 8 with persistent symptoms. Vital signs showed mild hypertension without orthostatic hypotension. Neurologic exam revealed postural instability, titubation, and inability to maintain seated posture with eyes closed. He had no dysmetria on finger-nose or heel-shin testing. Blood values were notable only for an elevated creatinine of 2.1 mg/dL. CT head revealed no acute pathology. MRI brain showed no infarct or recurrent disease. He was discharged home and symptoms resolved by day 10. Given clinical syndrome of truncal ataxia shortly after cytarabine, we diagnosed cytarabine-related neurotoxicity. Further cycles of consolidation were withheld for close observation. While cytarabine-related neurotoxicity is more common after an increased cumulative dose, it can occur after only a single cycle of 3 g/m2. Our patient’s age and baseline renal dysfunction likely predisposed him. Cytarabine dose-reduction can be considered in patients with these risk factors.
NIMG-107. THE LANDSCAPE OF BRAIN TUMOR MIMICS IN NEURO-ONCOLOGY PRACTICE
Authors: Lalanthica Yogendran, Tuba Kalelioglu, Joseph Donahue, Haroon Ahmed, Kester Phillips, Nicole Calautti, Maria-Beatriz Lopes, Ashok Asthagiri, Benjamin Purow, David Schiff, Sohil Patel, Camilo Fadul
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Differentiating neoplastic and non-neoplastic brain lesions is essential to make management recommendations and convey prognosis, but the distinction between brain tumors and their mimics in practice may prove challenging. The aim of this study is to provide the incidence of brain tumor mimics in the neuro-oncology setting and describe this patient subset. METHODS Retrospective study of adult patients referred to the Division of Neuro-oncology for a presumed diagnosis of brain tumor from January 1, 2005 through December 31, 2017, who later satisfied the diagnosis of a non-neoplastic entity based on neuroimaging, clinical course, and/or histopathology evaluation. We classified tumor mimic entities according to clinical, radiologic, and laboratory characteristics that correlated with the diagnosis. RESULTS The incidence of brain tumor mimics was 3.4% (132/3897). The etiologies of the non-neoplastic entities were vascular (35%), inflammatory non-demyelinating (26%), demyelinating (15%), cysts (10%), infectious (9%), and miscellaneous (5%). In our study, 38% of patients underwent biopsy to determine diagnosis, but in 26%, the biopsy was inconclusive. DISCUSSION Brain tumor mimics represent a small but important subset of the neuro-oncology referrals. Vascular, inflammatory, and demyelinating etiologies represent two-thirds of cases. Recognizing the clinical, radiologic and laboratory characteristics of such entities may improve resource utilization and prevent unnecessary as well as potentially harmful diagnostic and therapeutic interventions.
STEM-11. POLYAMINE METABOLISM AND INFLAMMATORY STATE CONTROL A VIRAL MIMICRY-DRIVEN QUIESCENT PHENOTYPE IN GLIOMA STEM CELLS (GSCS)
Authors: Charles Chesnelong, Connor Charton, Peter Dirks
Journal: Neuro-Oncology (2022)

Abstract The rate limiting enzyme of the polyamine pathway, SAT1, is significantly upregulated in non-cycling GSCs. However, higher SAT1 expression predicts poorer survival in GBM suggesting a role in quiescence and recurrence post-treatment. Treating GSCs with N1N11-Diethylnorspermine (DENSpm) recapitulates SAT1 upregulation and triggers a chemoprotective, long-term reversible growth arrest, while not affecting expression of stem, differentiation, nor senescence-associated markers. Remarkably, DENSpm strongly induces double-stranded RNA in GSCs. Interestingly, S-Adenosyl methionine (SAM) is an essential aminopropyl donor for polyamine biosynthesis. We found a significant correlation between DNA methylation, SAM, and polyamines across GSCs suggesting that SAM depletion may cause epigenetic and post-transcriptional alterations leading to re-activation of endogenous retroviral elements (ERVs) and viral mimicry-driven quiescence. However, while we confirmed DENSpm-induced SAM depletion, we did not detect DNA, histone, nor RNA demethylation. Noteworthy, ERVs are the most accessible transposable elements in GSCs indicative of a poised state. Furthermore, the correlation between expression of ERVs and interferon stimulated genes reveals a spectrum of viral mimicry amongst GSCs. Using a larger cohort of GSCs and hfNSCs, we identified three DENSpm response subgroups. A resistant subgroup comprised of cells able to proliferate through treatment, a reversible one whereby cells become quiescent and readily re-enter cell cycle post-treatment, and an irreversible consisting of cells that enter a deep quiescent state which they cannot escape. Importantly, we found that DENSpm response correlates with the cell's basal inflammatory state and the activity of viral defense pathways. These results indicate that a viral mimicry-driven quiescence may be specific to slower-growing neurodevelopmental GSCs, while more proliferative, inflammatory-poised GSCs are impervious to these additional cues. We propose that polyamine metabolism, glioma stem cell hierarchy and tumour inflammatory context play a central role in regulating quiescence and have important clinical implications in the initial response to treatment, aggressiveness, and ultimately recurrence of GBM.
EXTH-66. BIOENERGETIC SWITCH AND BIOLOGIC RESPONSE WITH SLC25A11 INHIBITION TARGETING MALATE-ASPARTATE SHUTTLE (MAS) ON GLIOBLASTOMA TUMORSPHERE
Authors: Hejoung Cho, Jihwan Yoo, Ran Joo Choi, Junseong Park, Seon-Jin Yoon, Yoojung Oh, Ju Hyung Moon, Eui Hyun Kim, Jong Hee Chang, Seok-Gu Kang
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Cancer cells depended on cytosolic nicotinamide adenine dinucleotide (NADH) transported into mitochondria via the malate-aspartate shuttle (MAS) for ATP production. KN612 (N-phenylmaleimide), a MAS inhibitor, is known to interfere with cancer growth by reducing ATP production, supported by several studies except on glioblastoma (GBM). Therefore, this study was designed to elucidate whether MAS could be an aimable target in GBM. METHODS: We compared expression levels of MAS conforming enzymes between normal and GBM samples. Gene expression profiles were analyzed using RNA-sequencing. Mitochondrial activity was measured by oxygen consumption (OCR), tetramethylrhodamine-ethylester (TMRE) staining, and liquid chromatograph-tandem mass spectrometer (LC-MS/MS). Also, biological functions were measured by cell viability, ATP levels, NADH levels, stemness, and invasiveness. In vivo efficacies were confirmed using a mouse orthotopic xenograft model. RESULTS: An analysis of the microarray database revealed that expression levels of several MAS enzymes including OGC (SLC25A11) were elevated in GBM. Through RNA sequencing, it was confirmed that KN612 accurately targeted SLC25A11 and decreased its expression. KN612-treated cells showed decreased viability, ATP production, and NADH levels compared with control cells. Under the same conditions, a significant decrease in stemness, invasion, and MMP was confirmed. In addition, KN612 confirmed remarkable therapeutic responses in a mouse orthotopic xenograft model. CONCLUSION: Our results show that KN612 effectively inhibits cancer cells both at the cellular level and at the in vivo level. This shows that targeting MAS could be a potential treatment option in addition to the currently limited standard GBM therapy.